Is AFF1 p.Val607Ile (c.1819G>A) pathogenic?

AFF1 p.Val607Ile (c.1819G>A) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0797); Rare (popmax 0.125%, afr).

How common is AFF1 p.Val607Ile (c.1819G>A) in the general population?

AFF1 p.Val607Ile (c.1819G>A) is rare (popmax 0.125%, afr) (gnomAD).

What do computational predictors say about AFF1 p.Val607Ile (c.1819G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

AFF1 p.Val607Ile

c.1819G>A · rs140196770 · VCV2597975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.71	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 2.1	GERP -0.3, phastCons 0.83
Regional constraint	o/e 1.07	unconstrained · MANE · 84 kb · p 0.031 · regional, not allelic
Overall
CADD	15.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V600I vs ClinVar V607I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.125% African / African-American · 80/63,762 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0951%

Overall 0.0081% 112/1,382,702 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.125%	797
East Asian	0.0501%	1,996
Finnishnot grpmax-eligible	0.0211%	4,736
Remaining individualsnot grpmax-eligible	0.00836%	11,961
Admixed American	0.00594%	16,827
European (non-Finnish)	0.000385%	259,687

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: AFF1
Protein: p.Val607Ile
Coding: c.1819G>A
MANE Select: NM_001166693
dbSNP: rs140196770
Type: single nucleotide variant
Location: chr4:87114652 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB
Residue 607: the 'disordered' region

Full AFF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF1 p.Val607Leu Uncertain significance ★ ⚠ same residue
AFF1 c.1191+8C>T Benign/Likely benign ★★ same type
AFF1 p.Ala40= Benign ★★ same type
AFF1 p.Pro393= Benign ★★ same type
AFF1 p.Ser627Cys Likely benign ★★ same type
AFF1 p.Thr426= Likely benign ★★ same type
AFF1 p.Val711Ile Benign ★★ same type
AFF1 p.Ala1047Val 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/aff1-p-val607ile (accessed [today's date]).

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