Is SRY p.Ala66Pro (c.196G>C) pathogenic?

SRY p.Ala66Pro (c.196G>C) is classified Likely pathogenic in SRY (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.903); Absent from gnomAD v4.1; Associated with 46 XY differences of sex development.

What condition is associated with SRY p.Ala66Pro (c.196G>C)?

SRY p.Ala66Pro (c.196G>C) is associated with 46 XY differences of sex development (ClinVar).

How common is SRY p.Ala66Pro (c.196G>C) in the general population?

SRY p.Ala66Pro (c.196G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SRY p.Ala66Pro (c.196G>C)?

AlphaMissense predicts likely pathogenic (score 0.903) — an in-silico prediction, not a clinical call.

SRY p.Ala66Pro

c.196G>C · rs2124486291 · VCV1177296

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.903 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

46 XY differences of sex development

Computational evidence

Protein change
AlphaMissense	0.903	likely pathogenic ✓ concordant with ClinVar
REVEL	0.715	pathogenic-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	phastCons 0.96
Regional constraint	o/e 0.47	unconstrained · MANE · 611 bp · p 0.0003 · regional, not allelic
Overall
CADD	22.3	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

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.Ala66Pro
Coding: c.196G>C
MANE Select: NM_003140
dbSNP: rs2124486291
Type: single nucleotide variant
Location: chrY:2787408 (GRCh38)
Structure: AlphaFold pLDDT 69.01 · 10 PDB
Residue 66: a DNA-binding region; the 'sufficient for interaction with kpnb1' region; the 'required for nuclear localization' region; an α-helix

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

Disease context

46 XY differences of sex development — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SRY p.Ser190Arg Benign 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.Cys40Ter Likely pathogenic ★ same type
SRY p.Gln111Ter Pathogenic ★ same type
SRY p.Gln57Ter 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-ala66pro (accessed [today's date]).

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