Is ESF1 p.Ile550Val (c.1648A>G) pathogenic?

ESF1 p.Ile550Val (c.1648A>G) is classified Uncertain significance in ESF1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0613); Rare (popmax 0.328%, afr).

How common is ESF1 p.Ile550Val (c.1648A>G) in the general population?

ESF1 p.Ile550Val (c.1648A>G) is rare (popmax 0.328%, afr) (gnomAD).

What do computational predictors say about ESF1 p.Ile550Val (c.1648A>G)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

ESF1 p.Ile550Val

c.1648A>G · VCV4251040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.328%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -4.88	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 0.36	GERP -4.2, phastCons 0.002
Regional constraint	o/e 0.93	unconstrained · MANE · 68 kb · p 0.033 · regional, not allelic
Overall
CADD	7.738	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.328% African / African-American · 246/75,020 alleles

Filtering AF 0.294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.0167% 270/1,613,626 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.328%	305
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Middle Eastern	0.0167%	5,986

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: ESF1
Protein: p.Ile550Val
Coding: c.1648A>G
MANE Select: NM_001276380
Type: single nucleotide variant
Location: chr20:13766795 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81
Residue 550: the 'disordered' region; a UniProt-annotated variant site (in)

Full ESF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NDUFAF5 c.-208C>T Benign ★★ same type
ESF1 p.Ala120Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala303Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala412Ser Uncertain significance ★ ⚠ same type
ESF1 p.Ala651Ser Uncertain significance ★ ⚠ same type
ESF1 p.Ala651Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala653Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala709Val 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/esf1-p-ile550val (accessed [today's date]).

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