Is PTDSS1 p.Phe112Val (c.334T>G) pathogenic?

PTDSS1 p.Phe112Val (c.334T>G) is classified Uncertain significance in PTDSS1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: ambiguous (0.4228); Very rare (popmax 0.00223%, eas); Associated with microcephaly.

What condition is associated with PTDSS1 p.Phe112Val (c.334T>G)?

PTDSS1 p.Phe112Val (c.334T>G) is associated with microcephaly (ClinVar).

How common is PTDSS1 p.Phe112Val (c.334T>G) in the general population?

PTDSS1 p.Phe112Val (c.334T>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PTDSS1 p.Phe112Val (c.334T>G)?

AlphaMissense predicts ambiguous (score 0.4228) — an in-silico prediction, not a clinical call.

PTDSS1 p.Phe112Val

c.334T>G · rs1275425796 · VCV813547

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

microcephaly

Computational evidence

Protein change
AlphaMissense	0.4228	ambiguous
REVEL	0.205	benign-leaning
SaProt	LLR -3.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 58 kb · p 3e-14 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 6.2e-05% 1/1,614,104 alleles · very rare exomes 1/1,461,768 · genomes 0/152,336 · joint denominator

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: PTDSS1
Protein: p.Phe112Val
Coding: c.334T>G
MANE Select: NM_014754
dbSNP: rs1275425796
Type: single nucleotide variant
Location: chr8:96287039 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.33 · 6 PDB
Residue 112: an α-helix

Full PTDSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PTDSS1 p.Arg95Gln Pathogenic/Likely pathogenic ★★ same type
PTDSS1 p.Ala140Thr Uncertain significance ★★ ⚠ same type
PTDSS1 p.Arg238Gln Uncertain significance ★★ ⚠ same type
PTDSS1 p.Glu212Lys Uncertain significance ★★ ⚠ same type
PTDSS1 p.Gly229Asp Uncertain significance ★★ ⚠ same type
PTDSS1 p.His246Gln Uncertain significance ★★ ⚠ same type
PTDSS1 p.Leu292Phe Uncertain significance ★★ ⚠ same type
PTDSS1 p.Leu307Trp Uncertain significance ★★ ⚠ same type

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/ptdss1-p-phe112val (accessed [today's date]).

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