Is PHIP p.Ala337Val (c.1010C>T) pathogenic?

PHIP p.Ala337Val (c.1010C>T) is classified Uncertain significance in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.6063); Very rare (popmax 0.00223%, eas).

How common is PHIP p.Ala337Val (c.1010C>T) in the general population?

PHIP p.Ala337Val (c.1010C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PHIP p.Ala337Val (c.1010C>T)?

AlphaMissense predicts likely pathogenic (score 0.6063) — an in-silico prediction, not a clinical call.

PHIP p.Ala337Val

c.1010C>T · rs760846343 · VCV624256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6063	likely pathogenic
REVEL	0.242	benign-leaning
SaProt	LLR -6.10	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 22 kb · p 1e-18 · regional, not allelic
Overall
CADD	29.7	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 0.00223% East Asian · 1/44,748 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.0013% 21/1,610,290 alleles · very rare exomes 19/1,458,600 · genomes 2/151,690 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,748
Admixed American	0.00167%	59,816
European (non-Finnish)	0.00144%	69,255
African / African-American	0.00134%	74,718
South Asian	0.0011%	90,888

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: PHIP
Protein: p.Ala337Val
Coding: c.1010C>T
MANE Select: NM_017934
dbSNP: rs760846343
Type: single nucleotide variant
Location: chr6:79017568 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 337: a UniProt-annotated variant site (in chujans)

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

Similar variants

PHIP p.Ala337= Likely benign ★ same residue
PHIP p.Arg110Cys Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg178Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg193Ter Pathogenic ★★ same type
PHIP p.Arg255Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg396Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg503Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg721Ter Pathogenic/Likely pathogenic ★★ 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/phip-p-ala337val (accessed [today's date]).

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