Is SIX5 p.Pro80Ser (c.238C>T) pathogenic?

SIX5 p.Pro80Ser (c.238C>T) is classified Conflicting classifications of pathogenicity in SIX5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0788); Low-frequency (popmax 1.28%, eas).

How common is SIX5 p.Pro80Ser (c.238C>T) in the general population?

SIX5 p.Pro80Ser (c.238C>T) is low-frequency (popmax 1.28%, eas) (gnomAD).

What do computational predictors say about SIX5 p.Pro80Ser (c.238C>T)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

SIX5 p.Pro80Ser

c.238C>T · rs934739524 · VCV1318014

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.2	GERP -0.35, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	20.7	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 1.28% East Asian · 408/31,960 alleles

Filtering AF 1.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.13%

Overall 0.0328% 424/1,294,442 alleles · low-frequency exomes 401/1,142,586 · genomes 23/151,856 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.28%	78
African / African-American	0.0202%	4,961
Remaining individualsnot grpmax-eligible	0.0041%	24,389
European (non-Finnish)	9.71e-05%	1,029,818

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.Pro80Ser
Coding: c.238C>T
MANE Select: NM_175875
dbSNP: rs934739524
Type: single nucleotide variant
Location: chr19:45768607 (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-pro80ser (accessed [today's date]).

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