Is PHGDH p.Ala43Pro (c.127G>C) pathogenic?

PHGDH p.Ala43Pro (c.127G>C) is classified Uncertain significance in PHGDH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-14). AlphaMissense: ambiguous (0.555); Very rare (popmax 0.000339%, nfe); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Ala43Pro (c.127G>C)?

PHGDH p.Ala43Pro (c.127G>C) is associated with PHGDH deficiency (ClinVar).

How common is PHGDH p.Ala43Pro (c.127G>C) in the general population?

PHGDH p.Ala43Pro (c.127G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PHGDH p.Ala43Pro (c.127G>C)?

AlphaMissense predicts ambiguous (score 0.555) — an in-silico prediction, not a clinical call.

PHGDH p.Ala43Pro

c.127G>C · rs1557962025 · VCV1901031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

PHGDH deficiency

Computational evidence

Protein change
AlphaMissense	0.555	ambiguous
REVEL	0.491	indeterminate
SaProt	LLR -11.63	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	23.9	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 0.000339% European (non-Finnish) · 4/1,179,976 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,956 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: PHGDH
Protein: p.Ala43Pro
Coding: c.127G>C
MANE Select: NM_006623
dbSNP: rs1557962025
Type: single nucleotide variant
Location: chr1:119712149 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB
Residue 43: an α-helix

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

Disease context

PHGDH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHGDH p.Ala43= Likely benign ★ same residue
PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.412-1G>C Likely pathogenic ★★ same condition
PHGDH c.643+1G>A Likely pathogenic ★★ same condition

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/phgdh-p-ala43pro (accessed [today's date]).

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