Is STRA6 p.Leu129Pro (c.386T>C) pathogenic?

STRA6 p.Leu129Pro (c.386T>C) is classified Uncertain significance in STRA6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-21). AlphaMissense: likely benign (0.0715); Ultra-rare (popmax 0.0438%, nfe); Associated with microphthalmia, syndromic 9.

What condition is associated with STRA6 p.Leu129Pro (c.386T>C)?

STRA6 p.Leu129Pro (c.386T>C) is associated with microphthalmia, syndromic 9 (ClinVar).

How common is STRA6 p.Leu129Pro (c.386T>C) in the general population?

STRA6 p.Leu129Pro (c.386T>C) is ultra-rare (popmax 0.0438%, nfe) (gnomAD).

What do computational predictors say about STRA6 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

STRA6 p.Leu129Pro

c.386T>C · rs139557843 · VCV317115

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0438%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

microphthalmia, syndromic 9

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.443	indeterminate
SaProt	LLR -5.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.23, phastCons 0.69
Regional constraint	o/e 0.91	unconstrained · MANE · 22 kb · p 0.0065 · regional, not allelic
Overall
CADD	14.96	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 0.0438% European (non-Finnish) · 517/1,179,972 alleles

Filtering AF 0.0407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0394%

Overall 0.0332% 536/1,613,742 alleles · ultra-rare exomes 512/1,461,734 · genomes 24/152,008 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0438%	2,282
Remaining individualsnot grpmax-eligible	0.0224%	4,462
African / African-American	0.00668%	14,972

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.Leu129Pro
Coding: c.386T>C
MANE Select: NM_022369
dbSNP: rs139557843
Type: single nucleotide variant
Location: chr15:74196028 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.18

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

Disease context

microphthalmia, syndromic 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STRA6 p.Leu129= Conflicting classifications of pathogenicity ★ 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.Arg467Cys 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-leu129pro (accessed [today's date]).

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