Is SMC5 p.Ile778Phe (c.2332A>T) pathogenic?

SMC5 p.Ile778Phe (c.2332A>T) is classified Uncertain significance in SMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.187); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMC5 p.Ile778Phe (c.2332A>T)?

SMC5 p.Ile778Phe (c.2332A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMC5 p.Ile778Phe (c.2332A>T) in the general population?

SMC5 p.Ile778Phe (c.2332A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMC5 p.Ile778Phe (c.2332A>T)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

SMC5 p.Ile778Phe

c.2332A>T · VCV3958688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 68 kb · p 0.0013 · regional, not allelic
Overall
CADD	22.1	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMC5
Protein: p.Ile778Phe
Coding: c.2332A>T
MANE Select: NM_015110
Type: single nucleotide variant
Location: chr9:70324078 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 4 PDB
Residue 778: a UniProt-annotated variant site (in atels2; loss-of-function variant; unable to rescue microcephaly and aberrant craniofacial patterning in zebrafish lacking smc5; loss of interaction with slf2, smc6 and nsmce2)

Full SMC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMC5 p.Glu226Lys Uncertain significance ★★ same condition
SMC5 p.Ala166Ser Uncertain significance ★ ⚠ same condition
SMC5 p.Ala615Val Uncertain significance ★ ⚠ same condition
SMC5 p.Ala735Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Ala791Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Ala870Thr Uncertain significance ★ ⚠ same condition
SMC5 p.Arg1031Trp Uncertain significance ★ ⚠ same condition
SMC5 p.Arg1091Gln Uncertain significance ★ ⚠ 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/smc5-p-ile778phe (accessed [today's date]).

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