Is DNAAF4 p.Phe247Leu (c.741C>A) pathogenic?

DNAAF4 p.Phe247Leu (c.741C>A) is classified Uncertain significance in DNAAF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-09). AlphaMissense: likely pathogenic (0.9721); Ultra-rare (popmax 0.0253%, sas); Associated with Inborn genetic diseases.

What condition is associated with DNAAF4 p.Phe247Leu (c.741C>A)?

DNAAF4 p.Phe247Leu (c.741C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DNAAF4 p.Phe247Leu (c.741C>A) in the general population?

DNAAF4 p.Phe247Leu (c.741C>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about DNAAF4 p.Phe247Leu (c.741C>A)?

AlphaMissense predicts likely pathogenic (score 0.9721) — an in-silico prediction, not a clinical call.

DNAAF4 p.Phe247Leu

c.741C>A · rs145991721 · VCV410964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9721	likely pathogenic · top 1% in DNAAF4
REVEL	0.342	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 68 kb · p 7.4e-05 · regional, not allelic
Overall
CADD	22.4	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 0.0253% South Asian · 23/91,042 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00229% 37/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,958
Middle Eastern	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.000678%	147,501

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.Phe247Leu
Coding: c.741C>A
MANE Select: NM_130810
dbSNP: rs145991721
Type: single nucleotide variant
Location: chr15:55450264 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAAF4 p.Ala391Val Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Arg233His Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Arg245Gln Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Arg410Leu Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Arg410Trp Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Gln4Arg Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Glu222Lys Uncertain significance ★★ ⚠ same condition
DNAAF4 p.Glu286Asp Uncertain significance ★★ ⚠ same condition

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-phe247leu (accessed [today's date]).

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