Is STRA6 p.Thr321Pro (c.961A>C) pathogenic?

STRA6 p.Thr321Pro (c.961A>C) is classified Uncertain significance in STRA6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.0987); Ultra-rare (popmax 0.0887%, nfe); Associated with STRA6-related disorder.

What condition is associated with STRA6 p.Thr321Pro (c.961A>C)?

STRA6 p.Thr321Pro (c.961A>C) is associated with STRA6-related disorder, microphthalmia, syndromic 9 (ClinVar).

How common is STRA6 p.Thr321Pro (c.961A>C) in the general population?

STRA6 p.Thr321Pro (c.961A>C) is ultra-rare (popmax 0.0887%, nfe) (gnomAD).

What do computational predictors say about STRA6 p.Thr321Pro (c.961A>C)?

AlphaMissense predicts likely benign (score 0.0987) — an in-silico prediction, not a clinical call.

STRA6 p.Thr321Pro

c.961A>C · rs118203962 · VCV1138

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0987 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0887%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STRA6-related disorder

Computational evidence

Protein change
AlphaMissense	0.0987	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -6.18	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 22 kb · p 0.0065 · regional, not allelic
Overall
CADD	23.2	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 0.0887% European (non-Finnish) · 1,044/1,177,044 alleles

Filtering AF 0.0842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0824%

Overall 0.0729% 1,172/1,607,106 alleles · ultra-rare exomes 1,110/1,454,862 · genomes 62/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0887%	1,127
South Asian	0.0636%	1,572
Remaining individualsnot grpmax-eligible	0.0562%	1,779
Finnishnot grpmax-eligible	0.0347%	2,879
African / African-American	0.0147%	6,813
Admixed American	0.00509%	19,627

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: STRA6
Protein: p.Thr321Pro
Coding: c.961A>C
MANE Select: NM_022369
dbSNP: rs118203962
Type: single nucleotide variant
Location: chr15:74189244 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.18
Residue 321: a UniProt-annotated variant site (in mcops9)

Full STRA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

STRA6-related disorder

Also linked: microphthalmia, syndromic 9

Similar variants

STRA6 p.Thr321= Likely benign ★ same residue
STRA6 c.267-1G>T Pathogenic/Likely pathogenic ★★ same condition
STRA6 p.Arg532Ter Pathogenic ★★ same condition
STRA6 p.Thr644Met Pathogenic ★★ ⚠ same condition
STRA6 c.*10A>C Uncertain significance ★★ same condition
STRA6 p.Ala54Ser Uncertain significance ★★ ⚠ same condition
STRA6 p.Ala557Val Uncertain significance ★★ ⚠ same condition
STRA6 p.Arg408Gly 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/stra6-p-thr321pro (accessed [today's date]).

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