Is SRY p.Pro83Thr (c.247C>A) pathogenic?

SRY p.Pro83Thr (c.247C>A) is classified Uncertain significance in SRY (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.8606); Absent from gnomAD v4.1; Associated with 46,XX sex reversal 1.

What condition is associated with SRY p.Pro83Thr (c.247C>A)?

SRY p.Pro83Thr (c.247C>A) is associated with 46,XX sex reversal 1 (ClinVar).

How common is SRY p.Pro83Thr (c.247C>A) in the general population?

SRY p.Pro83Thr (c.247C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SRY p.Pro83Thr (c.247C>A)?

AlphaMissense predicts likely pathogenic (score 0.8606) — an in-silico prediction, not a clinical call.

SRY p.Pro83Thr

c.247C>A · VCV4538406

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8606 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

46,XX sex reversal 1

Computational evidence

Protein change
AlphaMissense	0.8606	likely pathogenic
REVEL	0.671	pathogenic-leaning
SaProt	LLR -10.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 611 bp · p 0.0003 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SRY
Protein: p.Pro83Thr
Coding: c.247C>A
MANE Select: NM_003140
Type: single nucleotide variant
Location: chrY:2787357 (GRCh38)
Structure: AlphaFold pLDDT 69.01 · 10 PDB
Residue 83: a DNA-binding region; the 'sufficient for interaction with kpnb1' region

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

Disease context

46,XX sex reversal 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRY p.Pro83His Uncertain significance ★ ⚠ same residue
SRY p.Gln111Ter Pathogenic ★ same condition
SRY p.Thr102Ile Likely pathogenic ★ same condition
SRY p.Arg76Leu Likely pathogenic ★★ same type
SRY p.Ser155= Benign/Likely benign ★★ same type
SRY p.Ala113Glu Likely pathogenic ★ same type
SRY p.Ala113Val Likely pathogenic ★ same type
SRY p.Ala66Pro Likely pathogenic ★ ⚠ 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/sry-p-pro83thr (accessed [today's date]).

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