Is UNC80 p.Ser139Phe (c.416C>T) pathogenic?

UNC80 p.Ser139Phe (c.416C>T) is classified Uncertain significance in UNC80 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-21). AlphaMissense: likely benign (0.1542); Very rare (popmax 8.47e-05%, nfe); Associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2.

What condition is associated with UNC80 p.Ser139Phe (c.416C>T)?

UNC80 p.Ser139Phe (c.416C>T) is associated with hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (ClinVar).

How common is UNC80 p.Ser139Phe (c.416C>T) in the general population?

UNC80 p.Ser139Phe (c.416C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about UNC80 p.Ser139Phe (c.416C>T)?

AlphaMissense predicts likely benign (score 0.1542) — an in-silico prediction, not a clinical call.

UNC80 p.Ser139Phe

Q: How is Hypotonia-speech impairment-severe cognitive delay syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.416C>T · rs1237674284 · VCV1299434

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Computational evidence

Protein change
AlphaMissense	0.1542	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 57 kb · p 0.0051 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 0.000124% 2/1,614,170 alleles · very rare exomes 2/1,461,890 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	8.47e-05%	1,180,034

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: UNC80
Protein: p.Ser139Phe
Coding: c.416C>T
MANE Select: NM_001371986
dbSNP: rs1237674284
Type: single nucleotide variant
Location: chr2:209777375 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full UNC80 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypotonia, infantile, with psychomotor retardation and characteristic facies 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

UNC80 c.4110+1G>C Pathogenic/Likely pathogenic ★★ same condition
UNC80 c.8772+1G>A Likely pathogenic ★★ same condition
UNC80 p.Arg1076Ter Pathogenic ★★ same condition
UNC80 p.Arg1110Ter Pathogenic ★★ same condition
UNC80 p.Arg1285Ter Pathogenic ★★ same condition
UNC80 p.Arg1355Ter Pathogenic ★★ same condition
UNC80 p.Arg137Ter Pathogenic ★★ same condition
UNC80 p.Arg174Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/unc80-p-ser139phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown