Is SIX5 p.Ala660Val (c.1979C>T) pathogenic?

SIX5 p.Ala660Val (c.1979C>T) is classified Conflicting classifications of pathogenicity in SIX5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.119); Rare (popmax 0.115%, mid).

How common is SIX5 p.Ala660Val (c.1979C>T) in the general population?

SIX5 p.Ala660Val (c.1979C>T) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about SIX5 p.Ala660Val (c.1979C>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

SIX5 p.Ala660Val

c.1979C>T · rs376176843 · VCV2077626

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -7.45	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	19.03	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 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00869% 140/1,611,674 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Remaining individualsnot grpmax-eligible	0.0144%	6,940
South Asian	0.0121%	8,281
European (non-Finnish)	0.00898%	11,132
Finnishnot grpmax-eligible	0.0081%	12,346
Admixed American	0.00167%	60,010
African / African-American	0.00133%	74,930

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.Ala660Val
Coding: c.1979C>T
MANE Select: NM_175875
dbSNP: rs376176843
Type: single nucleotide variant
Location: chr19:45765742 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

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

Similar variants

SIX5 p.Ala660Glu Likely benign ★★ same residue
SIX5 p.Ala660Thr Benign/Likely benign ★★ same residue
SIX5 p.Ala660= Likely benign ★ same residue
SIX5 p.Ala408Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same type
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same type
SIX5 p.Ala649Ser 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/six5-p-ala660val (accessed [today's date]).

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