Is SIX5 p.Ala77Val (c.230C>T) pathogenic?

SIX5 p.Ala77Val (c.230C>T) is classified Uncertain significance in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-18). AlphaMissense: likely benign (0.0913); Ultra-rare (popmax 0.0126%, eas).

How common is SIX5 p.Ala77Val (c.230C>T) in the general population?

SIX5 p.Ala77Val (c.230C>T) is ultra-rare (popmax 0.0126%, eas) (gnomAD).

What do computational predictors say about SIX5 p.Ala77Val (c.230C>T)?

AlphaMissense predicts likely benign (score 0.0913) — an in-silico prediction, not a clinical call.

SIX5 p.Ala77Val

c.230C>T · rs1161188618 · VCV2548932

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0913 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0913	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.7	GERP -3.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	17.27	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

Grpmax group 0.0126% East Asian · 4/31,770 alleles

Filtering AF 0.00423% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00257%

Overall 0.00044% 5/1,136,766 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0126%	7,942
African / African-American	0.00155%	64,524

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: SIX5
Protein: p.Ala77Val
Coding: c.230C>T
dbSNP: rs1161188618
Type: single nucleotide variant
Location: chr19:45768615 (GRCh38)

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/six5-p-ala77val (accessed [today's date]).

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