Is BIRC6 p.Pro1735Ala (c.5203C>G) pathogenic?

BIRC6 p.Pro1735Ala (c.5203C>G) is classified Benign in BIRC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0611); Low-frequency (popmax 4.55%, amr).

How common is BIRC6 p.Pro1735Ala (c.5203C>G) in the general population?

BIRC6 p.Pro1735Ala (c.5203C>G) is low-frequency (popmax 4.55%, amr) (gnomAD).

What do computational predictors say about BIRC6 p.Pro1735Ala (c.5203C>G)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

BIRC6 p.Pro1735Ala

c.5203C>G · rs34906338 · VCV778258

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.55%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 69 kb · p 0.5 · regional, not allelic
Overall
CADD	18.26	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.55% Admixed American · 2,730/60,002 alleles

Filtering AF 4.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.35%

Overall 0.179% 2,894/1,613,838 alleles · low-frequency exomes 2,371/1,461,570 · genomes 523/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.55%	22
Remaining individualsnot grpmax-eligible	0.178%	563
African / African-American	0.056%	1,786
East Asian	0.00223%	44,888
European (non-Finnish)	0.000848%	117,980

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: BIRC6
Protein: p.Pro1735Ala
Coding: c.5203C>G
MANE Select: NM_016252
dbSNP: rs34906338
Type: single nucleotide variant
Location: chr2:32464770 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)

Full BIRC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BIRC6 p.Gln853Arg Uncertain significance ★★ ⚠ same type
BIRC6 p.Glu4506Asp Uncertain significance ★★ ⚠ same type
BIRC6 c.7409-6T>C Likely benign ★★ same type
BIRC6 p.Ala1549= Benign ★★ same type
BIRC6 p.Ala3622Val Likely benign ★★ same type
BIRC6 p.Ala4466= Benign/Likely benign ★★ same type
BIRC6 p.Arg4605= Benign ★★ same type
BIRC6 p.Asp4607= Benign ★★ 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/birc6-p-pro1735ala (accessed [today's date]).

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