Is DNAAF4 p.Val91Ile (c.271G>A) pathogenic?

DNAAF4 p.Val91Ile (c.271G>A) is classified Benign in DNAAF4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0673); Common (popmax 6.93%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DNAAF4 p.Val91Ile (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

DNAAF4 p.Val91Ile

Q: How common is DNAAF4 p.Val91Ile (c.271G>A) in the general population?

DNAAF4 p.Val91Ile (c.271G>A) is common (popmax 6.93%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.271G>A · rs17819126 · VCV416509

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.93%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.62	donor gain · deltas
Pangolin	Δ0.53	gain · loss 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.78	GERP 1.2, phastCons 0.21
Regional constraint	o/e 1.18	unconstrained · MANE · 68 kb · p 7.4e-05 · regional, not allelic
Overall
CADD	21.0	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 6.93% European (non-Finnish) · 81,423/1,175,422 alleles

Filtering AF 6.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.87%

Overall 6.06% 96,973/1,599,962 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	20.4%	5
European (non-Finnish)grpmax	6.93%	14
Remaining individualsnot grpmax-eligible	5.83%	17
Finnishnot grpmax-eligible	5.44%	18
South Asian	4.47%	22
Ashkenazi Jewishnot grpmax-eligible	4.33%	23
Middle Eastern	3.96%	25
Admixed American	3.41%	29
African / African-American	1.26%	80
East Asian	0.0313%	3,195

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DNAAF4
Protein: p.Val91Ile
Coding: c.271G>A
MANE Select: NM_130810
dbSNP: rs17819126
Type: single nucleotide variant
Location: chr15:55497712 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 91: a UniProt-annotated variant site (in); the 'mediates interaction with esr1 and stub1' region

Full DNAAF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAAF4 p.Val91Phe Uncertain significance ★ ⚠ same residue
DNAAF4 c.1047+1G>A Pathogenic/Likely pathogenic ★★ same type
DNAAF4 c.1153+1G>A Pathogenic ★★ same type
DNAAF4 c.405+1G>A Likely pathogenic ★★ same type
DNAAF4 p.Arg245Ter Pathogenic/Likely pathogenic ★★ same type
DNAAF4 p.Arg270Ter Pathogenic/Likely pathogenic ★★ same type
DNAAF4 p.Arg330Trp Pathogenic/Likely pathogenic ★★ same type
DNAAF4 p.Arg371Ter Pathogenic/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/dnaaf4-p-val91ile (accessed [today's date]).

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