Is PHF2 p.Val680Met (c.2038G>A) pathogenic?

PHF2 p.Val680Met (c.2038G>A) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely pathogenic (0.7706); Very rare (popmax 0.0022%, sas).

How common is PHF2 p.Val680Met (c.2038G>A) in the general population?

PHF2 p.Val680Met (c.2038G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PHF2 p.Val680Met (c.2038G>A)?

AlphaMissense predicts likely pathogenic (score 0.7706) — an in-silico prediction, not a clinical call.

PHF2 p.Val680Met

c.2038G>A · VCV3931529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7706	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 18 kb · p 7.2e-10 · regional, not allelic
Overall
CADD	29.4	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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,613,976 alleles · very rare exomes 8/1,461,786 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
African / African-American	0.00133%	74,932
European (non-Finnish)	0.000593%	168,578

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: PHF2
Protein: p.Val680Met
Coding: c.2038G>A
MANE Select: NM_005392
Type: single nucleotide variant
Location: chr9:93665786 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB

Full PHF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHF2 c.299+7T>A Benign ★★ same type
PHF2 c.789+10G>A Benign/Likely benign ★★ same type
PHF2 p.Asp103= Benign ★★ same type
PHF2 p.Leu645= Benign/Likely benign ★★ same type
PHF2 p.Pro786= Benign ★★ same type
PHF2 p.Pro988= Benign ★★ same type
PHF2 p.Ser725= Benign ★★ same type
PHF2 p.Ser738= Benign ★★ 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/phf2-p-val680met (accessed [today's date]).

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