Is BPIFA3 p.Val136Ile (c.406G>A) pathogenic?

BPIFA3 p.Val136Ile (c.406G>A) is classified Benign in BPIFA3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). AlphaMissense: likely benign (0.0587); Common (popmax 82.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with BPIFA3-related disorder.

What condition is associated with BPIFA3 p.Val136Ile (c.406G>A)?

BPIFA3 p.Val136Ile (c.406G>A) is associated with BPIFA3-related disorder (ClinVar).

What do computational predictors say about BPIFA3 p.Val136Ile (c.406G>A)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

BPIFA3 p.Val136Ile

Q: How common is BPIFA3 p.Val136Ile (c.406G>A) in the general population?

BPIFA3 p.Val136Ile (c.406G>A) is common (popmax 82.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.406G>A · rs3818222 · VCV3059896

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 82.2%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BPIFA3-related disorder

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.86	GERP -2.6
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.51 · regional, not allelic
Overall
CADD	0.01	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 82.2% East Asian · 36,860/44,854 alleles

Filtering AF 81.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.2%

Overall 54.6% 880,515/1,613,474 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	82.2%	1
African / African-American	74.9%	1
South Asian	64%	2
Remaining individualsnot grpmax-eligible	55.4%	2
Middle Eastern	53.3%	2
European (non-Finnish)	52.6%	2
Finnishnot grpmax-eligible	52.2%	2
Ashkenazi Jewishnot grpmax-eligible	46.1%	2
Amishnot grpmax-eligible	41.9%	2
Admixed American	38.3%	3

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: BPIFA3
Protein: p.Val136Ile
Coding: c.406G>A
MANE Select: NM_178466
dbSNP: rs3818222
Type: single nucleotide variant
Location: chr20:33225117 (GRCh38)
Gene constraint: LOEUF 1.511 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36
Residue 136: a UniProt-annotated variant site (in)

Full BPIFA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BPIFA3-related disorder

Similar variants

BPIFA3 p.Asp166Asn Likely benign same condition
BPIFA3 p.Cys165Ter Benign same condition
BPIFA3 p.Pro201Leu Benign ⚠ same condition
BPIFA3 p.Ser109Ter Benign same condition
BPIFA3 p.Ala140Val Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala20Ser Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala53Thr Uncertain significance ★ ⚠ same type
BPIFA3 p.Ala73Thr Uncertain significance ★ ⚠ 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/bpifa3-p-val136ile (accessed [today's date]).

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