Is ESF1 p.Val111Ala (c.332T>C) pathogenic?

ESF1 p.Val111Ala (c.332T>C) is classified Uncertain significance in ESF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.0658); Very rare (popmax 6.88e-05%).

How common is ESF1 p.Val111Ala (c.332T>C) in the general population?

ESF1 p.Val111Ala (c.332T>C) is very rare (popmax 6.88e-05%) (gnomAD).

What do computational predictors say about ESF1 p.Val111Ala (c.332T>C)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

ESF1 p.Val111Ala

c.332T>C · rs1980267605 · VCV2615852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.88e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.28	GERP -4.4
Regional constraint	o/e 0.93	unconstrained · MANE · 68 kb · p 0.033 · regional, not allelic
Overall
CADD	8.296	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 6.88e-05%

Overall 6.88e-05% 1/1,452,480 alleles · very rare

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.Val111Ala
Coding: c.332T>C
MANE Select: NM_001276380
dbSNP: rs1980267605
Type: single nucleotide variant
Location: chr20:13782809 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81
Residue 111: the 'disordered' region

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-val111ala (accessed [today's date]).

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